The development of a new pharmaceutical, from conception to readiness for marketing, typically costs hundreds of millions of dollars and takes many years. The development process starts with a step of matching a molecule (a potential pharmaceutical) to a target, e.g., a protein in a human body or in a microorganism. The matching of a molecule to a pharmaceutical is known as a drug lead, as it may lead to the development of a drug. The molecule is then modified to be more active, more selective and more pharmaceutically acceptable (e.g., less toxic and more easily administered). The failure rates at these stages are very high.
With the development of combinatorial chemistry and automated screening techniques, a new method of drug discovery has been developed. In this new method, a large library of molecules is chemically tested against a target, with the molecule having a best match being used as a starting point for finding a lead and/or as a lead. Some of these libraries are constructed empirically, for example, based on available molecules and/or molecules known to act as pharmaceuticals. Other libraries are constructed to have a wide a range as possible of different molecules. Other libraries are constructed so that individual molecules will have as great a chance as possible in matching a target. In general, molecules are selected to be as diverse as possible and to be drug like (e.g., size, chemical behavior) so that if a match is found it can serve as a lead.
Some references to such libraries and/or other discovery methods include, Pickett S.D. at al., J. Chem. Inf. Comput. Sci. 36(6), p. 1214-23 (1996) and Ferguson A. M. et al., J. Biomol. Scr. 1(2), p. 65 (1996), Bunin A. B. et. al., Proc. Natl. Acad. Sci. USA 91, p. 4708-12 (1994), Ellman J. et. al., Proc. Natl. Acad. Sci. USA 94, p. 2779-82 (1997) and Maly D. J. et. al., Proc. Natl. Acad. Sci. USA 97(6), p. 2419-24 (2000), the disclosures of which are incorporated herein by reference.
Another, virtual, structure based, type of screening is known. In the virtual method, a model of the target is generated (e.g., x-ray crystallography, estimated tertiary layout, analogy). Then, the affinity of a large number of molecules is determined by calculating docking behavior of a model of the molecule in the model of the target. Due to the relatively primitive state of molecular modeling and the resulting lack of availability of models, this method is not currently very successful.
Sunesis, inc., in D J Maly et al PNAS 97(6), p 2419-24(2000), the disclosure of which is incorporated herein by reference, suggest using large fragments of molecules as leads and then linking together such matching leads that are found into larger leads that are tested again for matching. The fragments are provided with pre-defined linkers, for the linking together.
PCT application PCT/US99/06734 (WO 99/49314), the disclosure of which is incorporated herein by reference, also describes a scheme of using fragments, and then linking the fragments to provide leads.